63: Miscellaneous Antihypertensives and Pharmacologically Related Agents
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63: Miscellaneous Antihypertensives and Pharmacologically Related Agents Jerome DeRoos Francis INTRODUCTION Hypertension is one of the commonest chronic medical problems and one of the most readily amenable to pharmacotherapy. Beginning in the 1960s, when asymptomatic hypertension was linked to significant adverse effects such as stroke, myocardial infarction, and sudden death, antihypertensive pharmacotherapeutics began being used. The first generation included centrally acting, sympatholytics, direct vasodilators, sodium nitroprusside, and diuretics. Unfortunately, these often had significant adverse events, leading to the development of β-adrenergic antagonists, calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and, more recently, direct renin inhibitors (DRIs). This chapter reviews the first-generation antihypertensives, as well ACEIs, ARBs, and DRIs. In general, the majority of antihypertensives manifest clinical signs and symptoms in terms of the degree of hypotension produced. Particular attention will be placed on mechanisms of action and unique toxicologic considerations for each of these xenobiotics. CLONIDINE AND OTHER CENTRALLY ACTING ANTIHYPERTENSIVES Clonidine is an imidazoline compound that was synthesized in the early 1960s. Because of its potent peripheral α2-adrenergic agonist effects, it was initially studied as a potential topical nasal decongestant. However, hypotension was a common adverse event, which redirected its consideration for other therapeutic applications.105 Clonidine is the best understood and the most commonly used of all the centrally acting antihypertensives, a group that includes methyldopa, guanfacine, and guanabenz. Although these drugs differ chemically and structurally, they all decrease blood pressure in a similar manner. The imidazoline compounds oxymetazoline and tetrahydrozoline, which are used as ophthalmic topical vasoconstrictors and nasal decongestants, produce similar systemic effects when ingested.105 Since 1985, the increased efficacy and improved adverse event profiles of the newer antihypertensives have diminished the use of the α2-adrenergic agonists in routine hypertension management. However, their use is increasing as a result of a wide variety of applications, including attention-deficit/hyperactivity disorder (ADHD), peripheral nerve and spinal anesthesia, and as an adjunct in the management of opioid, ethanol, and nicotine withdrawal.120,127,130,224 In addition, abuse of clonidine may be a growing problem in opioid dependent patients, and it has been used in criminal acts of chemical submission.20,145 Although centrally acting α2-adrenergic agonist exposure is relatively uncommon, it may cause significant toxicity, particularly in children. One report from two large pediatric hospitals identified 47 children requiring hospitalization for unintentional clonidine ingestions over a 5-year period.266 Significant clonidine poisoning has also resulted from formulation and dosing errors in children.211,241 Imidazolines used as ocular vasoconstrictors have resulted in significant systemic toxicity, especially when ingested.109,150,137,202 Pharmacology Clonidine and the other centrally acting antihypertensives exert their hypotensive effects primarily via 78,194,218,257 stimulation of presynaptic α2-adrenergic receptors in the brain. This central α2-adrenergic receptor agonism enhances the activity of inhibitory neurons in the vasoregulatory regions of the central nervous system (CNS), notably the nucleus tractus solitarius in the medulla, resulting in decreased norepinephrine release.217 This results in decreased sympathetic outflow from the intermediolateral cell columns of the thoracolumbar spinal tracts into the periphery2,256 and reduces the heart rate, vascular tone, and, ultimately, arterial blood pressure.186,256 This centrally mediated sympatholytic effect is modulated by nitric oxide and γ-aminobutyric acid (GABA), which may explain some of the clinical variability that occurs among patients who have overdosed with clonidine.37,87,234,260 Pharmacokinetics Clonidine is well absorbed from the gastrointestinal (GI) tract (~ 75%) with an onset of action within 30 to 60 minutes. The peak serum concentration occurs at 2 to 3 hours and lasts as long as 8 hours.59 Clonidine has 20% to 40% protein binding and an apparent volume of distribution of 3.2 to 5.6 L/kg.138 The majority of clonidine is eliminated unchanged via the kidneys.143 Clonidine is available in both oral and patch form. The patch, referred to as the clonidine transdermal therapeutic system, allows slow, continuous delivery of drug over a prolonged period of time, typically one week. This formulation, however, offers unique clinical challenges. Each patch contains significantly more drug than is typically delivered during the prescribed duration of use. For example, while a patch that delivers 0.1 mg/day of clonidine contains a total of 2.5 mg, the product that delivers 0.3 mg/day and contains a total of 7.5 mg.36 Even after one week of use, between 35% and 50% and, in some instances, as much as 70%, of the drug remains in the patch.36,98 Puncturing the outer membrane layer or backing opens the drug reservoir and allows a significant amount of the drug to be released rapidly. In addition, patients do not perceive this delivery system as a medication, and they may not exercise appropriate precautions. For example, discarding a used patch in an open wastebasket provides toddlers, who often are fascinated with stickers and other adhesive objects, an opportunity to remove the patch and apply, taste, or ingest it. Numerous reports of toxicity in both adults and children have resulted from dermal exposure, mouthing, or ingesting one clonidine patch, emphasizing this concern.36,47,98,102,124,204,205 Guanabenz and guanfacine are structurally and pharmacologically very similar to each other. They are well absorbed orally, achieving peak concentrations within 3 to 5 hours, and both have large volumes of distribution (4–6 L/kg for guanfacine, 7–17 L/kg for guanabenz).109,237 Whereas guanabenz is metabolized predominantly in the liver and undergoes extensive first-pass effect, guanfacine is eliminated equally by the liver and kidney.109,237 The metabolism of neither drug results in the production of significant active metabolites. Whereas clonidine, guanabenz, and guanfacine are all active drugs with direct α2-adrenergic agonist effects, methyldopa is a prodrug. It enters the CNS, probably by an active transport mechanism, before it is converted into its pharmacologically active degradation products.22 α- Methylnorepinephrine is the most significant of its metabolites, although α-methyldopamine and α- 75,101,210 methylepinephrine may also be important. These metabolites are direct α2-adrenergic agonists and impart their hypotensive effect as do the other centrally acting antihypertensives. Approximately 50% of an oral dose of methyldopa is absorbed, and peak serum concentrations are achieved in 2 to 3 hours.170However, because methyldopa requires metabolism into its active form, these concentrations have little correlation with its clinical effects. Methyldopa has a small volume of distribution (0.24 L/kg) and little protein binding (15%).170 It is eliminated in the urine, both as parent compound and after hepatic sulfation.179 Pathophysiology In therapeutic oral dosing, clonidine and the other centrally acting antihypertensives have little effect on the peripheral α2 receptors, the peripheral sympathetic nervous system, or the normal circulatory responses that occur with exercise or the Valsalva maneuver.169,183However, when serum concentrations increase above 2 ng/mL, as in the setting of intravenous (IV) administration or oral overdose, peripheral postsynaptic α2-adrenergic stimulation may occur, causing increased norepinephrine release and producing vasoconstriction and hypertension.44,53,173,243 This hypertension is short lived, however, because the potent centrally mediated sympathetic inhibition becomes the predominant effect, and hypotension ensues.4,154,168,210 Imidazoline specific binding sites are identified both in the rostral ventrolateral medulla and in coronary artery vascular smooth muscle and may be important in the clinical effects of these xenobiotics although there exact function has not been elucidated.210,248 Direct stimulation of these imidazoline binding sites appears to lower blood pressure 24,62 independent of central α2-adrenergic effects. Therefore, although their precise physiologic relationship has not been clearly elucidated, more evidence supports the concept that both imidazoline and α2-adrenergic receptors modulate the ability of clonidine, and presumably other centrally acting antihypertensives, to inhibit central norepinephrine release and the cardiovascular effects.25,62,99,163 Clinical Manifestations Although the majority of the published cases involve clonidine, the signs and symptoms of poisoning with any centrally acting antihypertensive are similar. The CNS and cardiovascular toxicity reflect an exaggeration of their pharmacologic action. Common signs include CNS depression, bradycardia, hypotension, and (occasionally) hypothermia.6,192,227,253 Most patients who ingest clonidine or the other similarly acting drugs manifest symptoms rapidly, typically within 30 to 90 minutes.266 The exception may be methyldopa, a prodrug, which requires metabolism to be activated, possibly delaying toxicity for hours.227,270